rs886039231

Positions:

• chr6-90571720-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_145331.3(MAP3K7):​c.208G>C​(p.Glu70Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAP3K7 NM_145331.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.80

Genes affected

MAP3K7 (HGNC:6859): (mitogen-activated protein kinase kinase kinase 7) The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase mediates the signaling transduction induced by TGF beta and morphogenetic protein (BMP), and controls a variety of cell functions including transcription regulation and apoptosis. In response to IL-1, this protein forms a kinase complex including TRAF6, MAP3K7P1/TAB1 and MAP3K7P2/TAB2; this complex is required for the activation of nuclear factor kappa B. This kinase can also activate MAPK8/JNK, MAP2K4/MKK4, and thus plays a role in the cell response to environmental stresses. Four alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Protein kinase (size 255) in uniprot entity M3K7_HUMAN there are 28 pathogenic changes around while only 6 benign (82%) in NM_145331.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-90571720-C-G is Pathogenic according to our data. Variant chr6-90571720-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 264699.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-90571720-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP3K7	NM_145331.3	c.208G>C	p.Glu70Gln	missense_variant	2/17	ENST00000369329.8
MAP3K7	NM_003188.4	c.208G>C	p.Glu70Gln	missense_variant	2/16
MAP3K7	NM_145332.3	c.208G>C	p.Glu70Gln	missense_variant	2/16
MAP3K7	NM_145333.3	c.208G>C	p.Glu70Gln	missense_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K7	ENST00000369329.8	c.208G>C	p.Glu70Gln	missense_variant	2/17	1	NM_145331.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Frontometaphyseal dysplasia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 03, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;.;.;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	-0.040	T
MutationAssessor	Benign	1.3	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;P;P;P
Vest4		0.65
MutPred		0.46		Gain of MoRF binding (P = 0.0422);Gain of MoRF binding (P = 0.0422);Gain of MoRF binding (P = 0.0422);Gain of MoRF binding (P = 0.0422);
MVP		0.88
MPC		2.6
ClinPred		0.98	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886039231; hg19: chr6-91281439;